Means for correcting insulin resistance

 

(57) Abstract:

The invention relates to the field of medicine. The invention consists in the application of Mexidol (2-ethyl-6-methyl-3-oksipiridina succinate) as a means for the correction of insulin resistance. Mexidol can improve the effectiveness of hypoglycemic and hypolipidemic drugs, because it has a direct effect on carbohydrate and lipid metabolism. A wide range of pharmacological activity of Mexidol allows to reduce the number entered in the complex with it's antibacterial, anti-inflammatory, fibrinolytic, anxiolytic, antidiabetic drugs, as well as the means of correcting lipid metabolism, which helps to reduce the frequency of adverse reactions. table 2.

The invention relates to the field of experimental and clinical medicine.

In many pathological conditions the body's sensitivity to insulin is reduced. So, it is celebrated in a variety of infections, acute and chronic inflammatory processes, burn injuries, schizophrenia, diseases of the blood, the hypothyrosis according to, thyrotoxicosis, the syndrome polikistozy ovaries, obesity, aging, diabetes, cardio-sosudistom disease // Physiol-Rev. - 1995 - Jul; 75(3): 473-86)

Insulin resistance (IR) can be defined as a condition in which at physiological concentrations of insulin, there is a decrease in the consumption of glucose by tissues. Insufficient consumption of glucose by the tissues leads to stimulation of cells and the development of compensatory hyperinsulinemia. The most important pathogenetic link IL is to increase the level of free fatty which can decrease insulin sensitivity and activate gluconeogenesis (Boden G. 1998. Free fatty acids (FFA), a link between obesity and insulin resistance. Frontiers in Bioscience 3, 169-175). Key factors of this syndrome are hyperglycemia, hyperinsulinemia, dyslipidemia (hypertriglyceridemia, hypercholesterolemia, increased low-density lipoproteins and decrease high-density lipoproteins) (G. Boden Role of fatty acids in the pathogenesis of insulin resistance and NIDDM // Diabetes -1997. - Vol. 46-N. 1 - P. 3-9), arterial hypertension.

Known drugs, correcting lipid metabolism: statins are inhibitors of HMG-COA reductase (mevacor, pravastatin, simvastatin), derived fibre acid (clofibrate, fenofibrate, bezafibrat, gemfibrozil), nicotinic acid and its derivatives (enduracin, acipimox), anion exchange resins (colestipol, cholestyramine, probase to a greater or lesser extent, reduce the level of triglycerides, the very low density lipoproteins, low-density lipoprotein and total cholesterol, increasing high-density lipoproteins. However, these drugs require constant use, which can lead to significant side effects: myositis, rhabdomyolysis (fibrates), a persistent elevation of transaminases ALT and AST, insomnia, convulsions, paraesthesia (statins), expansion of blood vessels of the face and the upper half of the body, hyperglycemia (nicotinic acid), obstipation, dyspepsia (anion exchange resin) (Lipid metabolism disorders and coronary heart disease: primary prevention, diagnosis, and therapy guidelines for general practice // G. Assman (Ed.). 2.,enl. Ed. - Munchen: MMV-Medizin-Verl.,1993, p. 115-128).

For the correction of insulin resistance is also used biguanides (Metformin) or thiazolidinedione derivatives (troglitazone, rezulin), dose and dosing frequency of which varies depending on the level of glycemia (Saltiel A. L., Olefsky J. M. Thiazolidionediones in the treatment of insulin resistance and type II diabetes // Diabetes - 1996 - Vol.45-N. 12-P. 1661 - 1669)

However, the use of these drugs has a number of disadvantages. Biguanides are of limited use in the pathology of the kidney, in addition, they can cause lactic acidosis. With long-term use of these drugs occurs a decrease in sensitivity to them, about the effectiveness of troglitazone (rezulin) in the correction of insulin resistance in obesity, diabetes mellitus type II, hypertension, however, this drug has not yet been applied in patients with chronic and acute inflammatory diseases acute surgical diseases (chronic and acute destructive pancreatitis, peritonitis), has not yet received information about long-term use of this drug, in addition, the drug is contraindicated in liver (Nolan J. J., Ludvik Century, E. Beerdsen et al. Improvement in glucose tolerance and insulin resistance in obese subjects, treated with troglitazone //N. Engl. J. Mec. -1994-331-P. 1188-1193).

For the correction of insulin resistance in diabetes type 2 diabetes use insulin short and long-term actions, and dosage and administration frequency select only under the control of glycemia (Yki-Jarvinen H., Kaupi la m, Kujansuu E. et al. Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus // N. Engl. J. Med. - 1992 - Vol.327 - P. 426-1433).

However, the use of insulin for correction of insulin resistance in diabetes mellitus type 2 has several disadvantages: multiple times during the day introduction of insulin requires a well-regulated diet and amount of physical activity; the need for continuous and frequent monitoring of blood glucose for adequate insulin therapy; the use of high doses of insulin in the background already the MENA, and, therefore, may not be the best way to relieve insulin resistance. Increased risk of developing acute vascular disease (myocardial infarction, stroke) questioned the necessity of the use of insulin for correction of R & d, especially in patients of advanced age.

Mexidol (2-ethyl-6-methyl-3-oksipiridina succinate) is an antihypoxic drug, an inhibitor of free-radical processes, has strong anti-inflammatory and antibacterial properties, antiamnesic and anxiolytic action. Mexidol was used for the treatment of acute disorders of cerebral circulation, discirculatory encephalopathy, vascular dystonia, atherosclerotic disorders of brain function, neurotic disorders, inflammatory processes of different etiology.

Mexidol was not previously used as a means for the correction of insulin resistance, despite the low toxicity and a wide range of pharmacological activity.

Object of the invention is the expansion of the range of medicines that have the property of correction of insulin resistance, no contraindications and allowing to reduce the frequency FOB is uncinata) as a means for the correction of insulin resistance.

The use of Mexidol as a means for the correction of insulin resistance allows to obtain the following technical result.

The drug "Mexidol allows you to expand the range of drugs with properties correction of insulin resistance. Significantly expands the scope of application of the drug in a variety of infections, schizophrenia, blood diseases, diabetes, cardiovascular diseases, acute and chronic inflammation, obesity.

This Mexidol allow to increase the effectiveness of hypoglycemic and hypolipidemic drugs, because it has a direct effect on carbohydrate and lipid metabolism.

A wide range of pharmacological activity of Mexidol allows to reduce the number entered in the complex with it's antibacterial, anti-inflammatory, fibrinolytic, anxiolytic, antidiabetic drugs, as well as the means of correcting lipid metabolism, which helps to reduce the frequency of adverse reactions.

Mexidol virtually no side effects, so it can be applied by patients over 70 years of age and adolescents.

Use of the drug "Mexidol" has the man as the main pathogenetic link insulin resistance. Mexidol through the influence of the coupling of respiration and oxidative phosphorylation can be stimulated by direct oxidation of glucose in the pentose-phosphate shunt, stabilizing glutathione-glutationreductaza system and activate metabolic processes in the endoplasmic reticulum, promote the metabolism of fatty acids, phospholipids, prostaglandins. Important properties of Mexidol is its ability to enhance detoxification processes, to improve the rheological properties of the blood, stimulate the humoral link of nonspecific protection, provide anti-inflammatory and antibacterial effects. All of the above gives grounds to consider Mexidol as a promising drug for the correction of metabolic disorders (including insulin resistance) in various diseases (obesity, and cerebral infarction, ischemic heart disease, diabetes).

The drug is well combined with hypoglycemic drugs, lipid-lowering, anti-inflammatory drugs, fibrinolytic and thrombolytic drugs, as well as tools that have an impact on blood rheology.

The possibility of correcting Mexicola the Insa is found insulin resistance, is achieved through a direct effect on lipid metabolism through the mobilization of lipids from the fat depots with subsequent oxidation of fatty acids. This reduces the level of free fatty acids, normalization ratio atherogenic and antiatherogenic lipoprotein fractions (decrease lipoproteins of low and very low density and increase high-density lipoprotein), lower concentrations of triglycerides and total cholesterol in the blood. In addition, Mexidol increases tissue sensitivity to insulin by stimulating the direct oxidation of glucose in the pentose-phosphate shunt, thereby reducing glucosetolerance in relation to the glucose transporters (particularly GLUT4), insulin receptors and enzymes.

Apply Mexidol as a means for the correction of insulin resistance as follows.

Depending on the severity of the disorders of carbohydrate and lipid metabolism Mexidol injected into the body intramuscularly and/or oral. The dose depends on the disease stage and severity of its course. On average, Mexidol is administered in a dose of 100-200 mg daily for 5-7 days for a course of treatment, if necessary, repeat after 2-4 months. For example, nutramigen within 3-5 days. Possible oral (capsule form) with atherosclerosis of the coronary arteries, the vessels of the brain in diabetes mellitus type 2, 100 mg 2 times a day for 5-7 days.

Example 1. Patient C., 65 years.

Was admitted with complaints of dry mouth, aching pain in the legs at night.

At the examination: height 163 see Weight 84 kg, the skin is a normal color, dry. In the lungs vesicular breathing, wheezing no. Heart sounds rhythmic, muted, accent of II tone of the aorta. AD-150/80 mm RT.article The heart rate of 68 beats/min Abdominal palpation painless and soft in all departments, the liver is not enlarged. The lumbar area is not visually changed, symptom tapping negative on both sides, dysuria no.

Diagnosis: diabetes of the 2nd type, moderate. The stage of decompensation. Obesity class II).

Clinical and laboratory studies:

(before treatment with Mexidol)

CBC - without pathology

Clinical urine analysis showed no pathology

Blood biochemistry: ALT - 45 IU/l, ACT - 27 IU/l, alkaline phosphatase - 106 IU/l, XC - 6,92 mmol/l, TG - 3.88 mmol/l, creatinine - 86 Ámol/l, urea - 6,6 Glycemic profile: 900with 12.3, 12, 0mm; 1300- 11,9, 11,8; 1700and 12.4, and 12.5; 2100- 13,5, 12,7; 600to 12.5 and 11.2.

Consultation of the oculist: Diabetic retinopathy stages I-II. Palpate both eyes. Ongoing therapy: Diet N 8 (1800 kcal), glurenorm 0.3 2 tab. morning and evening, Enap 10 mg 1 tab. in the morning, mazindol 0.001 mg - 1 t/day acetylsalicylic acid 1/4 t in the morning.

Given the lack of effect of therapy glucose-lowering drugs, the patient was offered a transfer to insulin. In connection with failure patients on insulin therapy, it was decided to appoint Mexidol. Mexidol has appointed intramuscularly at a dose of 200 mg/day for 3 days, followed by oral administration of 100 mg for the next 4 days (1000 mg per treatment). To assess therapeutic effect of Mexidol were cancelled mazindol and acetylsalicylic acid. The patient continued to take glurenorm 0.3 2 tab. morning and evening, Enap 10 mg 1 tab. morning.

The treatment efficacy was observed on day 5 after administration of Mexidol and was expressed in the following:

The glycemic profile:

on the 5th day - 900- 7,2; 1300- 6,9; 1700- 6,7; 2100- 7,1; 600- 8.1 (mmol/l) blood glucose profile on the 10th day after receiving Mexidol: 9

The glycemic profile on the 12th day of the 900- 6,7; 1300- 6,1; 1700- 6,4; 2100- 6,6; 600- 7,5 (mmol/l)

on the 15th day of the 900- 5,7; 1300- 6,6; 1700- 6,2; 2100- 6,3; 600- 7,1 (mmol/l)

Biochemical analysis of blood (see tab. 1).

Examination by ophthalmologist:

Negative dynamics in the fundus of the eye during the test observations.

The patient was discharged from the hospital with a diagnosis of diabetes mellitus type 2, moderate in state compensation. Diabetic microangiopathy: diabetic retinopathy stages I-II. Diabetic distal polyneuropathy form touch type. Alimentary obesity class II).

Patient recommended: a diet low in animal fats and refined carbohydrates (1800 kcal), pragian 1 t in the morning and evening; Enap 10 mg 1 tab. in the morning. A second course of Mexidol is supposed to spend 2 months. Frequency of courses will depend on the condition of the patient (assessment of the level of glycemia, lipid spectrum and level IRI).

Example 2. Patient M., 46 years old.

Was admitted with complaints of acute encircling the pain in the left pojebani, vomiting.

When the inspection is Mary, muted, the accent of II tone of the aorta. AD-160/85 mm RT.article Heart rate is 90 beats/min Abdominal palpation painful tightening of the muscles of the abdominal wall in all departments, the liver is not enlarged. The lumbar area is not visually changed, symptom tapping negative on both sides, dysuria no.

Diagnosis (intraoperative): Acute hemorrhagic pancreatic necrosis. Enzymatic peritonitis. Intoxication, 2-sided jet pleurisy.

Clinical and laboratory studies:

(before treatment with Mexidol)

CBC - hemoglobin -102, ESR 68, the remaining indicators without pathology

Clinical urine analysis showed no pathology

Blood biochemistry: ALT - 27 IU/l, AST - 11 IU/l, alkaline phosphatase - 84 IU/l, LDL - 6,88 mmol/l, TG - 3.58 mmol/l, creatinine - 102 Ámol/l amylase blood - 907 g/CASL (N 25-80)

The glycemic profile: 900- 11,9; 1300- 12,4; 1700- 11,9; 2100- 12,8; 60011.2 in.

Ultrasound at receipt: Liver - without a pathology. Gall bladder 6,h,8 cm, thickened wall of the lumen homogeneous. Choledoch has a bend, not expanded. The pancreas is almost not visualized due to pneumatization loops of bowel, the head 33 mm, multiple heterogeneous structure.

Laporan, edematous.

Conclusion: acute fatty pancreonecrosis.

Emergency surgery: Laparotomy. Sequestrectomy. Cholecystostomy. Drainage stuffing bags. Sanitation and drainage stuffing bags. Pancreas: in the area of head, body and tail of the necrotic tissue black, large number of plaques stefanakos.

Held in the postoperative period therapy:

Mexidol - 200 mg intramuscularly 2 times a day for 4 days, contrical, Actovegin, gentamicin, vitamin therapy (standard dose)

The treatment efficacy was celebrated on the 5th day of reception of Mexidol and was expressed in the following:

The glycemic profile:

on the 5th day - 900- 6,7; 1300- 7,7 1700- 6,2; 2100- 7,4; 600- 7,1(mmol/l)

The glycemic profile on the 10th day after receiving Mexidol: 900- 6,1; 1300- 5,8; 1700- 6,0; 2100- 5,9; 600- 5,4 (mmol/l)

on the 14th day of the 900- 4,6; 1300- 5,8; 1700- 4,5; 2100- 5,5; 600- 4,7 (mmol/l)

on the 15th day of the 900- 4,3; 1300- 5,2; 1700- 5,0; 2100- 4,8; 600- 4,0 (mmol/l)

on the 30th day 900- 4,3; 1300- 5,3; 1700and 4.4; 2100- 4,7; 600to 4.5 (m is imicheskij blood (see table. 2).

Ultrasound on day 14 after surgery: Pancreas is visualized bad in the body thickened up to 42 mm, moderately heterogeneous. Saved a small amount of fluid in the spleen and in the pleural cavity.

Ultrasound at 30 days after surgery: Liver, gall bladder intact. The pancreas is poorly visualized in the body and tail. Free liquid is determined only by the spleen, pleural cavity free.

Ultrasound at 60 days after surgery: a Positive trend. Pancreas agogino heterogeneous, HH mm Free liquid not determined. Changes retroperitoneal space is not revealed.

In connection with the stabilization of the state, elimination of acute inflammation and its associated insulin resistance, the patient was discharged in satisfactory condition.

The use of Mexidol (2-ethyl-6-methyl-3-oksipiridina succinate) as a means for the correction of insulin resistance.

 

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